EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors

Abstract

Background: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival ,3 years; STS) and long term survivors (survival .3 years; LTS) of MPM. Methods: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology. Results: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. Conclusion: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively.

Novel systemic therapy against malignant pleural mesothelioma

“…Normal mesothelial cells express PDGFR-α while mesothelioma tumors express both PDGF-AA and PDGF-BB ligands as well as PDGFR-α and PDGFR-β (86)(87)(88). While the staining pattern of PDGFR-β immunoreactivity in frozen sections of MPM are consistent with MPM tumor cell expression of PDGFR-β, the function of PDGFR-β within tumor cells, as opposed to the associated stroma, has not been well described.…”

Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas

“…The patients were divided into two groups using 36 months as cutoff survival. Twenty-six patients were identified as long survivors (LS; one USA, one UK, one Austria, three France, five Turkey, 15 Italy) and 22 as short survivors (SS; five UK, eight Italy, nine Austria) [27].…”

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

“…Moreover, recent studies showed that adipocytes, circulating multipotential fibrocytes and adult bone marrow-derived stem cells are able to differentiate into both epithelial and mesenchymal cells [61][62][63]. Interestingly, mesothelial cells also have the ability to change phenotype to become smooth muscle cells and fibroblasts in internal organs and their vasculature, so normal mesothelial cells are multipotential, similar to stem cells [64].…”